Qualification, Validation, and Verification 2

By: David A. Porter
FDA provides a definition of validation in numerous documents. One such document, Guidance for Industry: Analytical Procedures and Methods Validation Chemistry, Manufacturing, and Controls Documentation says "methods validation is the process of demonstrating that analytical procedures are suitable for their intended use" (5). There also are numerous documents defining validation within the context of processes. From FDA's Guideline on General Principles of Process Validation:
"Validation—Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes (6)."
The same definition is provided in other FDA documents, such as Guideline on Sterile Drug Products Produced by Aseptic Processing. FDA document Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations provides this definition:
"With proper design (see section IV.C.1), and reliable mechanisms to transfer process knowledge from development to commercial production, a manufacturer should be able to validate the manufacturing process. In a quality system, process validation provides initial proof, through commercial batch manufacture, that the design of the process produces the intended product quality (7). "The remainder of the discussion about validation in this article will be restricted to a discussion of method validation.
Does it suit its purpose? The foregoing is clearly not an exhaustive list of the manners in which validation has been defined. It does appear that a recurring theme among the various definitions pertains to demonstrating that the method or process is suitable for its intended use. In this article, consider validation to be the demonstration that a method or process is suitable for its intended purpose. Accepting that, it is imperative that the intended purpose of a method or process is clearly stated at the outset of the validation. An example of the importance of such a statement can be found in Chapter ‹71› "Sterility Tests" (1). It states that "the following procedures are applicable for determining whether a Pharmacopeial article purporting to be sterile complies with the requirements set forth in the individual monograph with respect to the test for sterility." The next paragraph states
"These Pharmacopeial procedures are not by themselves designed to ensure that a batch of product is sterile or has been sterilized. This is accomplished primarily by validation of the sterilization process or of the aseptic processing procedures."
During the years there has been concern that the tests for sterility as provided in Chapter ‹71› are not adequate to prove that a batch of product is sterile. As stated previously, the tests in Chapter ‹71› were intended only to show that a Pharmacopeial article is sterile. Such a demonstration constitutes a necessary but not sufficient condition for sterile pharmacopeial articles. If one were to validate an alternative procedure for that in Chapter ‹71›, it would not be necessary to develop one that is intended to demonstrate sterility of an entire lot of product.
In addition, it is appropriate that the conditions are provided under which the validation was performed. Given that there are essentially countless variations on experimental conditions, product matrix effects, and so forth, a validation cannot reasonably expect to address all such permutations. For example, Method 3 in the section of Chapter ‹1047› "Biotechnology-Derived Articles—Tests", which addresses assays for total protein, indicates in a note:
"[Do not use quartz (silica) spectrophotometer cells: the dye binds to this material. Because different protein species may give different color response intensities, the standard protein and test protein should be the same.] There are relatively few interfering substances, but detergents and ampholytes in the test specimen should be avoided. Highly alkaline specimens may interfere with the acidic reagent (1)."